DESCRIPTION (from the applicant's abstract): The purpose of this project is to continue our use of quantitative measures from MRI to chart the longitudinal course of atrophy in specific brain structures at all stages of HD, as well as to develop new functional MRI techniques for studying activity of basal ganglia during tasks that elicit performance deficits in HD subjects. A major focus of this work is the development and validation of methodologies that can be used as outcome measures in future treatment trials, for both symptomatic and presymptomatic individuals who carry the HD gene mutation. We expect to demonstrate that volumetric MRI measures of basal ganglia are as good or better than the clinical measures currently used as outcome measures in clinical trials with symptomatic HD patients, and that MRI measures will be better than clinical measures for trials that involve presymptomatic carriers of the HD gene mutation. Furthermore, we hypothesize that functional MRI measures may be even more sensitive than volumetric measures to the earliest changes in basal ganglia in the presymptomatic stages of HD. The data collected in the proposed project should allow us to determine when basal ganglia abnormalities begin, which may be a good indicator of when treatment should begin. We will also compare rates of longitudinal change for the structural and functional MRI measures with rates of change for clinical and neuropsychological measures, to determine the relative strength of each of these variables as outcome measures in clinical trials at different stages of disease progression. By determining associations between decline in clinical, behavioral, and neuropsychological functions with changes in structural and functional measures that may deteriorate at different rates and at different points during the course of the illness, we will be able to provide a more complete picture of brain-behavior relationships in HD, which, in turn, will help us understand more fully brain-behavior relationships in general.